Asthma affects >300 million people worldwide. Both genetic and environmental factors contribute to risk, but interactions between them are poorly understood. Our studies in COAST children have identified significant gene-environment interactions (GEIs) and at least two independent pathways of risk for human rhinovirus (HRV)-associated wheezing illness in infancy and asthma onset in childhood. One pathway is associated with genotype at the 17q21 asthma locus and a second is associated with allergic sensitization in the first three years of life, expression of FCSRI receptors on peripheral blood dendritic cells, and genotype at the FCERIA locus. Moreover, genotype at the vitamin D receptor (VDR) locus is independently associated with duration and severity of HRV illness in older children. The overall objectives of this proposal are to study global transcriptional (RNA) and epigenetic (methylation) responses to human rhinovirus (HRV) infection in nasal epithelial cells (NECs) from COAST children, and further characterize both 17q21-dependent and 17q21-independent pathways of response. These studies will identify expression quantitative trait loci (eQTLs) and methylation (me)QTLs in HRV-infected and/or in mock-infected NECs, a relevant primary cell model. All functional variants (eQTLs and meQTLs) will be further evaluated for associations with phenotypes assessed in COAST children from birth through adolescence. Lastly, we will build networks of correlated transcriptional responses to characterize the impact of HRV infection on the molecular system in NECs. To our knowledge, these studies will be the first to use a systems genetic approach to elucidate the mechanisms underlying multiple pathways of risk for asthma and to characterize the molecular interactions between genetic and environmental risk factors for asthma in relevant, primary cells. The results of these studies will significantly impact our understanding of asthma pathogenesis, provide a new paradigm for elucidating function in asthma genetics, and potentially identify new pathways for the prevention and treatment of childhood asthma.